title: Identification of epithelial stromal interaction 1 as a novel effector downstream of Krüppel-like factor 8 in breast cancer invasion and metastasis.
abstract: Krüppel-like factor 8 (KLF8) is a transcriptional factor critical for metastatic progression of breast cancer. Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast-induced gene in non-invasive breast cancer cells is highly overexpressed in invasive breast carcinomas. The function and regulation of EPSTI1, however, remain largely unknown. In this paper, we report a novel KLF8 to EPSTI1 signaling pathway in breast cancer. Using various expression analyses, we revealed a high co-overexpression of KLF8 and EPSTI1 in invasive human breast cancer cells and patient tumors. Ectopic overexpression of KLF8 in the non-invasive MCF-10A cells induced the EPSTI1 expression, whereas KLF8 knockdown from the invasive, MDA-MB-231 cells decreased the EPSTI1 expression. Promoter activation and binding analyses indicated that KLF8 promoted the EPSTI1 expression by directly acting on the EPSTI1 gene promoter. EPSTI1 knockdown dramatically reduced the KLF8-promoted MCF-10A cell invasion, and ectopic expression of EPSTI1 in the non-invasive MCF-7 cells is sufficient to induce the cell invasion. Experiments using nude mice demonstrated that the ectopic EPSTI1 granted the MCF-7 cells capability of both invasive growth in the breasts and metastasis to the lungs. Using co-immunoprecipitation coupled with mass spectrometry, we discovered that EPSTI1 interacts with the valosin-containing protein (VCP), resulting in the degradation of IκBα and subsequent activation of NF-κB in the nucleus. These findings suggest a novel KLF8 to EPSTI1 to VCP to NF-κB signaling mechanism potentially critical for breast cancer invasion and metastasis.
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Lahiri
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Wason
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000556:secondary; D018797:Cell Cycle Proteins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; C459199:EPSTI1 protein, human; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse